Epidermal Growth Factor, (EGF), which is present in the intestinal lumen from breast milk and saliva, influences intestinal differentiation, although the mechanisms by which these effects are achieved remain obscure. Preliminary data demonstrate the presence of specific EGF receptors and tyrosine kinase activity in fetal and adult rat intestinal microvillus membrane (MVM). The proposed studies will test the hypothesis that luminal EGF enhances intestinal proliferation by binding to villus MVM receptors which modulate MVM phosphorylation and transepithelial transport of EGF for subsequent interaction with proliferating crypt cells, presumably at basolateral membrane (BLM) receptors. Evidence for this hypothesis will be obtained using morphological and biochemical techniques, including autoradiography, LM and EM immunocytochemistry, (125I)-EGF binding to specific membrane domains (MVM and BLM) and immunoprecipitation of labeled EGF receptor from MVM. To ascertain the role of both MVM and BLM EGF receptors in signal transduction, tyrosine kinase activity and substrate specificity will be studied in each membrane domain as well as in intact intestine after exposure to both luminal and serosal EGF.